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Cessation of denosumab treatment is associated with increases in bone turnover above baseline values and rapid bone loss. We investigated the efficacy of zoledronate to prevent this bone loss in women with postmenopausal osteoporosis who were treated with denosumab (mean duration 2.2 years) and discontinued treatment after achieving osteopenia. Women were randomized to receive a single zoledronate 5 mg infusion (n = 27) or two additional denosumab 60 mg injections (n = 30). Both groups were followed for a total period of 24 months. At 24 months LS-BMD was not different from baseline in the ZOL group, but decreased in the Dmab group by 4.82 ± 0.7% (p < 0.001) from the 12-month value; the difference in BMD changes between the two groups, the primary endpoint of the study, was statistically significant (p = 0.025). Results of FN-BMD changes were similar. Zoledronate infusion was followed by small but significant increases in serum Procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) during the first year and stabilization thereafter. In the denosumab group, bone turnover marker values did not change during the first 12 months but increased significantly at 15 months and in the majority of women these remained elevated at 24 months. Neither baseline nor 12-month bone turnover marker values were associated with BMD changes in either group of women. In the denosumab group, 3 patients sustained vertebral fractures (2 patients multiple clinical, 1 patient morphometric) while 1 patient in the zoledronate group sustained clinical vertebral fractures 12 months after the infusion. In conclusion, a single intravenous infusion of zoledronate given 6 months after the last Dmab injection prevents bone loss for at least two years independently of the rate of bone turnover. Follow-up is recommended, as in a few patients ZOL treatment might not have the expected effect at 2 years. This article is protected by copyright. All rights reserved.

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OBJECTIVE: Familial Paget's disease of bone is inherited as an autosomal-dominant trait and mutations in the sequestosome 1 (SQSTM1) gene have been reported with variable frequency in patients with familial disease. The natural history, however, of the disease in family members with or without SQSTM1 mutations is unknown. METHODS: To address this question, we investigated members of families with Paget's disease identified and genotyped in 2000 in The Netherlands without clinical, biochemical or radiological signs of Paget's disease. Seventy-five subjects, median age 56â¯years (range 44-93), with or without SQSTM1 mutations participated in the present study. Medical history was obtained and clinical examination and laboratory investigations were performed in all. When serum biochemical markers of bone turnover were increased, skeletal scintigraphy with SPECT-CT was performed. RESULTS: After a mean period of 15.9â¯±â¯0.32 (SD) years no subject without SQSTM1 mutations (either from positive or negative families) developed Paget's disease. Of 14 carriers of SQSTM1 mutations, Paget's disease of the pelvis was diagnosed in a 74-year old asymptomatic woman. CONCLUSION: The incidence of new Paget's disease in SQSTM1 positive subjects was 7.1% and no mutation-negative subject developed the disease within 16â¯years of follow-up. Subjects without SQSTM1 mutations can be reassured whereas mutation carriers should consider screening. Our findings should be confirmed in other populations as currently unknown environmental factors that might be involved in the development of the disease may differ.

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CONTEXT: Fibrous dysplasia/McCune Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates but clinical and biochemical responses may be incomplete. OBJECTIVE: To evaluate the efficacy and tolerability of the RANKL inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. DESIGN: Case series. SETTING: Academic Center of Expertise for Rare Bone Diseases. PATIENTS: Data was collected from twelve consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median 8.8 years) and were treated with subcutaneous Denosumab 60 mg at 3 or 6 monthly intervals with a follow up for at least 12 months. Main outcome(s)Sustained reduction of BTMs and bone pain. RESULTS: Denosumab 60 mg once every 3 months, but not once every 6 months, induced a sustained, significant reduction of BTMs. After a median treatment period of 15.5months (range 12-19) serum alkaline phosphatase activity and P1NP levels were respectively reduced from 212±39.4 IU/l to 79±6.0 IU/l (p=0.004) and from 346.2±111.1 ng/ml to 55.7±16.6 ng/ml (p=0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. CONCLUSION: Our results indicate that denosumab 60 mg 3-monthly is a promising, well-tolerated treatment for most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

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CONTEXT: Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event. OBJECTIVE: To assess information on invasive oral procedures and events (OPEs)-dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery-during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases. DESIGN: Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension. SETTING: Multicenter, multinational clinical trial. PATIENTS: Postmenopausal women with osteoporosis. INTERVENTIONS: Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab. MAIN OUTCOME MEASURES: Self-reports of OPEs and adjudicated cases of ONJ. RESULTS: Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%). CONCLUSIONS: Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment.

RESUMO

Paget's disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis though in recent years its prevalence and severity appear to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood.

RESUMO

The WNT signalling pathway is a key regulator of bone metabolism, particularly bone formation, which has helped to define the role of osteocytes - the most abundant bone cells - as orchestrators of bone remodelling. Several molecules involved in the control of the WNT signalling pathway have been identified as potential targets for the development of bone-building therapeutics for patients with osteoporosis. Several of these molecules have been investigated in animal models, but only inhibitors of sclerostin (which is produced by osteocytes) have been investigated in phase III clinical studies. Here, we review the rationale for these developments and the specificity and potential off-target actions of WNT-based therapeutics. We also describe the available preclinical and clinical studies and discuss the benefits and risks of using sclerostin inhibitors for the management of patients with osteoporosis.

RESUMO

Purpose: In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods: Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results: Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions: Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.

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Sclerostin is a 190 amino acid protein secreted primarily by osteocytes. It was initially identified due to mutations in the SOST gene associated with high bone mass phenotypes. Much recent work has sought to determine the importance of sclerostin across an array of conditions which affect the human skeleton. However, accurate measurement of sclerostin from serum and plasma sources remains a significant impediment, with currently available commercial assays showing marked differences in measured sclerostin values. Accordingly, sclerostin assay standardization remains an important but unmet need before sclerostin measurements can be used for the clinical management of bone disease. Here we characterize a novel automated chemiluminescent sclerostin assay (LIAISON®, DiaSorin) which overcomes many of these limitations. Important assay characteristics include: a wide dynamic range (50-6500pg/mL); high intra- (<2.5%) and inter- (<5%) assay precision; matched serum and plasma equivalence (<10% difference); specificity for the intact sclerostin molecule; and rapid assay results. Serum sclerostin levels measured with the LIAISON® assay in a population-based sample of adult men (n=278) and women (n=348) demonstrated that sclerostin levels were significantly higher in men as compared to women and were positively associated with age in both sexes, consistent with previously published work. In postmenopausal women, serum sclerostin levels measured with the LIAISON® assay were reduced in response to treatment with either estrogen or teriparatide, again consistent with previous findings. Collectively, the above data demonstrate that the LIAISON® sclerostin assay provides a reliable tool for more confident assessment of emergent mechanisms wherein sclerostin may impact a number of bone related pathologies.

RESUMO

BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.

RESUMO

BACKGROUND: Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. METHODS: To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. RESULTS: Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (-1.9 and -2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). CONCLUSION: The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. TRIAL REGISTRATION: ClincalTrials.gov registration number NCT00523341 ; registered August 30, 2007.

RESUMO

OBJECTIVE: To test the hypothesis that rebound of bone remodeling is responsible for clinical vertebral fractures reported in a few patients with osteoporosis after cessation of denosumab treatment. DESIGN: In this case-control study we compared clinical and biochemical characteristics of postmenopausal women with clinical vertebral fractures 8-16 months after the last injection of denosumab (Dmab/Fx+, n = 5) with those of treatment-naïve women with such fractures (Fx+, n = 5). In addition, 5 women who discontinued denosumab treatment but did not sustain vertebral fractures 18-20 months after the last injection were studied (Dmab/Fx-, n = 5). METHODS: We measured serum microRNAs, gene expression of mRNAs of factors regulating formation and activity of osteoclasts and biochemical markers of bone and mineral metabolism. In Dmab/Fx+ and Fx+ women, blood was taken 4-8 weeks after the fracture. RESULTS: Compared to Fx+ women, Dmab/Fx+ women had higher serum P1NP and CTx levels, and significantly lower serum miR-503 and miR-222-2 that downregulate osteoclastogenesis and osteoclast activity, and higher RANK (13-fold) and CTSK (2.6-fold) mRNA. The respective values of Dmab/Fx- women were in the same direction as those of Dmab/Fx+ women but of a lesser magnitude. CONCLUSIONS: Bone fragility in women with clinical vertebral fractures after stopping denosumab therapy is pathophysiologically different from that of treatment-naïve women with osteoporosis and clinical vertebral fractures and it is associated with upregulation of markers of osteoclast formation and activity. The small number of women with this rare event studied is a limitation.

RESUMO

Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.

RESUMO

The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.

RESUMO

During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis.

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